Despite decades of research, little is known about how to effectively prevent postoperative delirium or postoperative cognitive dysfunction; however, emerging perspectives on the role of the blood-brain barrier (BBB) in health and disease suggest that increased permeability (BBB dysfunction) may be associated with the development of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Up to half of all older adults develop POD, and POCD is reported in 5-20% of surgical patients over 65 years; at present, neither condition can be effectively prevented nor treated and both are associated with decreased quality of life and survival, as well as numerous other negative outcomes. Our long-term goal is to advance knowledge of the effects of surgical stress on the aging brain, ultimately leading to effective strategies to improve the cognitive safety of surgery. The objective of this research is to investigate the extent to which an innovative brain imaging technique, water exchange index MRI (WEI-MRI) evidence of BBB dysfunction predicts the incidence of POD and POCD, in a longitudinal study of older adults undergoing major elective non-cardiac surgeries. Our central hypothesis is that in the aging brain, BBB dysfunction is a biomarker for brain vulnerability that predicts increased risk for POD, POCD, and progressive cognitive decline. We will test this hypothesis by accomplishing the following specific aims: 1) Evaluate associations between BBB permeability and the incidence of POD; 2) Evaluate associations between BBB permeability and the incidence of POCD; and 3) Identify changes in markers of endothelial injury and inflammation in peripheral blood that predict POD and POCD. This approach is innovative because it employs a noninvasive technology to precisely measure BBB permeability and pinpoint the area(s) of the brain in which it occurs. The proposed research is significant in that it will lay essential groundwork for development of future interventions to improve the cognitive safety of major elective surgeries in the aging population. Recognition of BBB dysfunction may be of critical prognostic importance in determining brain susceptibility to surgical stress.